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Molecular Mechanisms of Dopaminergic Neuronal Protection by Regulation of Proteasome Activity

蛋白酶体活性调节保护多巴胺能神经元的分子机制

基本信息

批准号：
16590823
负责人：
SAWADA Hideyuki
金额：
$ 2.18万
依托单位：
Utano National Hospital, Clinical Research Center (2005)Kyoto University (2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Neurodegenerative disorders including Parkinson disease have common features, selective neuronal death and accumulation of insoluble proteins in the neurons. In Parkinson disease these two features are selective dopaminergic neuronal death and the appearance of alpha-synuclein positive Lewy bodies. In the previous research of Grant-in-Aid for Scientific Research (14570591), we reported that proteasome inhibition causes alpha-synuclein-positive inclusions, and on the contrary, it blocks dopaminergic neuronal death (Sawada et al., J.Biol.Chem.279:10710,2004). In this research we investigated the effect of proteasome inhibition on dopaminergic neuronal degeneration in vivo using animal hemi-Parkinson model by 6-hydroxy dopamine (6-OHDA). Histological analysis revealed that proteasome inhibition blocks dopaminergic neuronal degeneration in this model, and behavioral analysis showed that hemi-Parkinsonism is blocked by proteasome inhibition (Inden et al., J.Pharmacol.Sci.97:203-211,2005). These results seem paradoxical because previous hypothesis suggest that accumulation of insoluble proteins could cause dopaminergic neuronal degeneration.In this research we investigated the molecular mechanisms of neuroprotection by proteasome inhibition and found that proteasome inhibition elevated heat shock protein 70 (HSP7O) and glutathione (submitted and revised). In addition we reported that dopaminergic neuronal death by 6-OHDA is mediated by p-quinone, toxic dopamine intermediates (Izumi et al. J.Neurosci.Res. 79:849,2005;Izumi et al., J.Neurosci.Res.82:126-137,2005). Furthermore, we reported that sympathetic norepinephrine neuronal terminals in the papillary sphincter muscles are disturbed in patients in the disease (Sawada et al., JAMA 293:932-924,2005).

包括帕金森病在内的神经退行性疾病具有共同的特征，即选择性神经元死亡和神经元中不溶性蛋白的积累。在帕金森病中，这两个特征是选择性多巴胺能神经元死亡和α-突触核蛋白阳性路易体的出现。在科学研究补助金（14570591）的先前研究中，我们报道了蛋白酶体抑制引起α-突触核蛋白阳性包涵体，相反，它阻断多巴胺能神经元死亡（Sawada et al.，J.Biol.Chem.279：10710，2004）。本研究采用6-羟基多巴胺（6-OHDA）建立偏侧帕金森病动物模型，探讨蛋白酶体抑制对体内多巴胺能神经元变性的影响。组织学分析显示，蛋白酶体抑制阻断了该模型中的多巴胺能神经元变性，并且行为分析显示，蛋白酶体抑制阻断了偏侧帕金森症（Inden et al.，J.Pharmacol.Sci.97：203- 211，2005）。这些结果似乎是矛盾的，因为以前的假设认为，不溶性蛋白质的积累可能会导致多巴胺能神经元变性。在本研究中，我们研究了蛋白酶体抑制神经保护的分子机制，发现蛋白酶体抑制升高热休克蛋白70（HSP 70）和谷胱甘肽（提交和修订）。此外，我们报道了6-OHDA引起的多巴胺能神经元死亡是由对苯醌、毒性多巴胺中间体介导的（Izumi等人，J.Neurosci.Res.79：849，2005;Izumi等人，J.Neurosci.Res.82：126- 137，2005）。此外，我们报道了乳头括约肌中的交感去甲肾上腺素神经元末梢在疾病患者中受到干扰（Sawada等人，JAMA 293：932- 924，2005）。